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Lookup NU author(s): Professor Bobby McFarlandORCiD, Professor Robert TaylorORCiD
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© 2026 Published by Elsevier Inc. Isolated mitochondrial complex III deficiency can result from pathogenic variants in several nuclear or mitochondrial genes, encoding structural subunits or assembly factors of the enzyme. It is a rare cause of mitochondrial phenotypes with clinically heterogeneous presentations. Pathogenic variants in the Tetratricopeptide Repeat Domain 19 (TTC19) gene have been identified as a cause of mitochondrial complex III deficiency, nuclear type 2 (MIM #615157). We report 10 patients from five unrelated Arab families, all presenting with variable severity of a progressive neurodegenerative disorder characterized by loss of ambulation, speech impairment, and cognitive regression. Long-term clinical follow-up, supported by serial neuroradiological imaging, demonstrated progressive disease evolution, further highlighting the degenerative nature of the condition. In this cohort, exome sequencing (ES) identified three distinct pathogenic variants in the TTC19 gene across the five unrelated families, highlighting both genetic heterogeneity and regional clustering. In a Saudi family, A novel in-frame TTC19 variant NM_017775.4:c.680_709del; p.(Glu227_Leu236del) was identified, resulting in the loss of 10 amino acids in the protein. The second variant, NM_017775.4:c.779_780del; p.(Tyr260*), is a frameshift deletion leading to truncation of the TTC19 protein. This recurrent variant was identified in three independent Syrian families (Families 2, 3, and 4). The third variant, NM_017775.4:c.153_156del; p.(Arg52Alafs*48), also a frameshift variant, was detected in a fifth family of Kuwaiti origin. These loss of function TTC19 variants are proposed to underlie the observed phenotypes, as supported by mitochondrial functional studies, and contribute to the expanding spectrum of TTC19-related disorders, with specific variants recurring in particular regional or ethnic populations.
Author(s): Alghamdi M, Alahmad A, Alaboudi M, Alsheikh S, Alanazy MH, Albash B, Alaqeel A, Almontashiri NA, Jamjoom D, Bashiri FA, Hamad MH, Ali HH, Alwatidi M, Alharbi E, Omar S, Marafi D, Alabdulrazzaq F, Arold ST, McFarland R, Taylor R
Publication type: Article
Publication status: Published
Journal: Molecular Genetics and Metabolism
Year: 2026
Volume: 148
Issue: 2
Print publication date: 02/06/2026
Online publication date: 09/03/2026
Acceptance date: 23/02/2026
ISSN (print): 1096-7192
ISSN (electronic): 1096-7206
Publisher: Academic Press Inc.
URL: https://doi.org/10.1016/j.ymgme.2026.109867
DOI: 10.1016/j.ymgme.2026.109867
PubMed id: 41818954
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